Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website http://www.cardiologyres.org

Original Article

Volume 11, Number 5, October 2020, pages 319-327

Cyclophilins in Ischemic Heart Disease: Differences Between Acute and Chronic Coronary Artery Disease Patients

Figure 1. Serum Crps levels ((a) CypA, (b) CrpB, (c) CypC, (d) CypD) in patients with CAD and the relationship with traditional cardiovascular risk factors. Frequency plots: data represented as Cyp levels in x-axis, versus traditional cardiovascular risk factors (hypertension, dyslipidemia, smoking, gender, diabetes and age > 50 years) in y-axis. CAD: coronary artery disease; Crps: cyclophilins.

**Table 1.** Demographic and Clinical Characteristics
	Controls (n = 45)	Coronary artery disease	P value
LVEF: left ventricular ejection fraction; AAS: acetylsalicylic acid; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft; LDL: low-density lipoprotein; HDL: high-density lipoprotein; TG: triglycerides; hsCRP: high sensitivity C-reactive protein; ALT: alanine aminotransferase; WBC: white blood cells; SEM: standard error of the mean. ^aSevere milking in left anterior descending coronary artery. Data values are shown as mean ± SEM. Significant differences: P < 0.05.
Gender (male)	51.1% (23)	82.5% (33)	87.5% (35)	< 0.001	< 0.001	0.531	0.002
Age	45.6 ± 1.5	65.2 ± 1.8	64.2 ± 1.9	< 0.001	< 0.001	0.713	< 0.001
LVEF (%)	-	54.2 ± 10.3	55.6 ± 8.7	-	-	0.528	-
Cardiovascular risk factors
Hypertension	6.7% (3)	60.0% (24)	47.5% (19)	< 0.001	< 0.001	0.262	< 0.001
Dyslipidemia	13.3% (6)	77.5% (31)	67.5% (27)	< 0.001	< 0.001	0.317	< 0.001
Active smoker	4.5% (2)	17.5% (7)	37.5% (15)	0.001	0.002	0.045	0.079
Diabetes	2.2% (1)	35% (14)	20% (8)	< 0.001	0.001	0.248	< 0.001
Family history of CAD	4.4% (2)	12.5% (5)	17.5% (7)	0.768	0.651	0.531	0.616
Medications
AAS	0% (0)	77.5% (31)	15% (6)	< 0.001	< 0.001	< 0.001	< 0.001
Clopidogrel	0% (0)	12.5% (12)	7.5% (3)	0.04	0.05	0.712	0.020
Statins	11.1% (5)	75% (30)	42.5% (17)	< 0.001	< 0.001	0.003	0.100
Number of coronary artery vessels with significant stenosis
0	0 (0%)	2.5% (1)^a	0% (0)	< 0.001	< 0.001	0.219	< 0.001
1	0 (0%)	35% (14)	47.5% (19)
2	0 (0%)	22.5% (9)	30% (12)
3	0 (0%)	40.5 (16)	22.5% (9)
Type of coronary artery revascularization
None	100% (45)	7.5% (3)	2.5% (1)	< 0.001	< 0.001	0.405	< 0.001
PCI	0% (0)	82.5% (33)	92.5% (37)
CABG	0% (0)	10% (4)	5% (2)
Complete coronary artery revascularization
Yes	0% (0)	40% (16)	70% (28)	< 0.001	< 0.001	0.007	< 0.001
Laboratory parameters
Total cholesterol (mg/dL)	201.14 ± 26.98	149.7 ± 33.06	177.05 ± 41.55	< 0.001	< 0.001	0.006	< 0.001
LDL (mg/dL)	120.77 ± 24.44	81.85 ± 26.32	108.0 ± 34.17	< 0.001	< 0.001	0.001	< 0.001
HDL (mg/dL)	57.77 ± 15.28	41.15 ± 7.91	36.53 ± 7.95	< 0.001	< 0.001	0.024	< 0.001
TG (mg/dL)	107.17 ± 40.16	133.78 ± 45.91	164.0 ± 69.69	< 0.001	< 0.001	0.053	0.018
hsCRP (mg/dL)	0.49 ± 0.5	8.33 ± 11.64	43.45 ± 45.31	0.001	0.007	0.050	0.040
ALT (U/L)	22.06 ± 2.38	33.14 ± 19.47	33.32 ± 22.75	0.029	0.008	0.973	0.013
WBC (number/µL)	6,632.35 ± 320.45	7,305.25 ± 1,958.07	10,383.50 ± 4,732.36	< 0.001	< 0.001	< 0.001	0.155
Lymphocytes (number/µL)	2,139.39 ± 113.98	2,030.75 ± 788.78	1,982.50 ± 1,167.70	0.806	0.539	0.829	0.599
Neutrophils (number/µL)	3,757.58 ± 293.36	4,347.5 ± 1,543.06	7,462.50 ± 4,238.39	< 0.001	< 0.001	< 0.001	0.112
Monocytes (number/µL)	548.48 ± 23.08	641.75 ± 222.98	730.00 ± 315.58	0.010	0.037	0.153	0.047
Hemoglobin (g/dL)	13.88 ±1.30	14.33 ± 1.54	14.65 ± 1.54	0.068	0.037	0.326	0.145
Platelet (number/µL)	229,147 ± 52,606	188,250.0 ± 55,290.72	221,925.0 ± 77,988.62	0.013	0.072	0.029	0.002
Glucose (mg/dL)	90.5 ± 32.4	120.28 ± 48.55	110.8 ± 19.97	0.002	0.001	0.259	0.002

Table 1. Demographic and Clinical Characteristics

Controls (n = 45)

Coronary artery disease

P value

Chronic (n = 40)

Acute (n = 40)

Between three groups

CAD vs. controls

Chronic CAD vs. acute CAD

Chronic CAD vs. controls

LVEF: left ventricular ejection fraction; AAS: acetylsalicylic acid; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft; LDL: low-density lipoprotein; HDL: high-density lipoprotein; TG: triglycerides; hsCRP: high sensitivity C-reactive protein; ALT: alanine aminotransferase; WBC: white blood cells; SEM: standard error of the mean. ^aSevere milking in left anterior descending coronary artery. Data values are shown as mean ± SEM. Significant differences: P < 0.05.

Gender (male)

51.1% (23)

82.5% (33)

87.5% (35)

< 0.001

0.531

0.002

Age

45.6 ± 1.5

65.2 ± 1.8

64.2 ± 1.9

< 0.001

0.713

< 0.001

LVEF (%)

54.2 ± 10.3

55.6 ± 8.7

0.528

Cardiovascular risk factors

Hypertension

6.7% (3)

60.0% (24)

47.5% (19)

< 0.001

0.262

< 0.001

Dyslipidemia

13.3% (6)

77.5% (31)

67.5% (27)

< 0.001

0.317

< 0.001

Active smoker

4.5% (2)

17.5% (7)

37.5% (15)

0.001

0.002

0.045

0.079

Diabetes

2.2% (1)

35% (14)

20% (8)

< 0.001

0.001

0.248

< 0.001

Family history of CAD

4.4% (2)

12.5% (5)

17.5% (7)

0.768

0.651

0.531

0.616

Medications

AAS

0% (0)

77.5% (31)

15% (6)

< 0.001

Clopidogrel

0% (0)

12.5% (12)

7.5% (3)

0.04

0.05

0.712

0.020

Statins

11.1% (5)

75% (30)

42.5% (17)

< 0.001

0.003

0.100

Number of coronary artery vessels with significant stenosis

0 (0%)

2.5% (1)^a

0% (0)

< 0.001

0.219

< 0.001

0 (0%)

35% (14)

47.5% (19)

0 (0%)

22.5% (9)

30% (12)

0 (0%)

40.5 (16)

22.5% (9)

Type of coronary artery revascularization

None

100% (45)

7.5% (3)

2.5% (1)

< 0.001

0.405

< 0.001

PCI

0% (0)

82.5% (33)

92.5% (37)

CABG

0% (0)

10% (4)

5% (2)

Complete coronary artery revascularization

Yes

0% (0)

40% (16)

70% (28)

< 0.001

0.007

< 0.001

Laboratory parameters

Total cholesterol (mg/dL)

201.14 ± 26.98

149.7 ± 33.06

177.05 ± 41.55

< 0.001

0.006

< 0.001

LDL (mg/dL)

120.77 ± 24.44

81.85 ± 26.32

108.0 ± 34.17

< 0.001

0.001

< 0.001

HDL (mg/dL)

57.77 ± 15.28

41.15 ± 7.91

36.53 ± 7.95

< 0.001

0.024

< 0.001

TG (mg/dL)

107.17 ± 40.16

133.78 ± 45.91

164.0 ± 69.69

< 0.001

0.053

0.018

hsCRP (mg/dL)

0.49 ± 0.5

8.33 ± 11.64

43.45 ± 45.31

0.001

0.007

0.050

0.040

ALT (U/L)

22.06 ± 2.38

33.14 ± 19.47

33.32 ± 22.75

0.029

0.008

0.973

0.013

WBC (number/µL)

6,632.35 ± 320.45

7,305.25 ± 1,958.07

10,383.50 ± 4,732.36

< 0.001

0.155

Lymphocytes (number/µL)

2,139.39 ± 113.98

2,030.75 ± 788.78

1,982.50 ± 1,167.70

0.806

0.539

0.829

0.599

Neutrophils (number/µL)

3,757.58 ± 293.36

4,347.5 ± 1,543.06

7,462.50 ± 4,238.39

< 0.001

0.112

Monocytes (number/µL)

548.48 ± 23.08

641.75 ± 222.98

730.00 ± 315.58

0.010

0.037

0.153

0.047

Hemoglobin (g/dL)

13.88 ±1.30

14.33 ± 1.54

14.65 ± 1.54

0.068

0.037

0.326

0.145

Platelet (number/µL)

229,147 ± 52,606

188,250.0 ± 55,290.72

221,925.0 ± 77,988.62

0.013

0.072

0.029

0.002

Glucose (mg/dL)

90.5 ± 32.4

120.28 ± 48.55

110.8 ± 19.97

0.002

0.001

0.259

0.002

**Table 2.** Cyclophilins and Inflammatory Markers
	Controls	Coronary artery disease	P value
CAD: coronary artery disease; Cyp: cyclophilin; IFN-γ: interferon γ; IL: interleukin; TNF-α: tumor necrosis factor α; MMP: metalloproteinase; SEM: standard error of the mean. Data values are shown as mean ± SEM. Significant differences: P < 0.05.
Cyclophilins (Cyps)
CypA (ng/mL)	2.53 ± 0.53	5.52 ± 0.759	7.80 ± 1.30	< 0.001	< 0.001	0.134	0.001
CypB (pg/mL)	140.2 ± 32.7	181.0 ± 28.2	208.8 ± 44.8	0.387	0.204	0.601	0.353
CypC (pg/mL)	9.38 ± 1.5	30.56 ± 4.7	34.28 ± 5.8	< 0.001	< 0.001	0.620	< 0.001
CypD (pg/mL)	125.14 ± 20.5	117.74 ± 11.5	97.68 ± 10.7	0.433	0.431	0.205	0.756
CypC > 17.5 (pg/mL)	13.3% (6)	57.5% (29)	72.5% (23)	< 0.001	< 0.001	0.245	< 0.001
Inflammatory markers
IFN-γ (pg/mL)	34.3 ± 2.8	27.5 ± 2.4	27.4 ± 2.7	0.102	0.032	0.989	0.73
IL-1β (pg/mL)	2.71 ± 0.17	3.94 ± 0.42	3.73 ± 0.37	0.012	0.001	0.695	0.009
IL-2 (pg/mL)	4.38 ± 0.44	4.87 ± 0.52	4.97 ± 0.51	0.648	0.356	0.891	0.473
IL-6 (pg/mL)	4.04 ± 0.33	3.95 ± 0.59	8.08 ± 1.59	0.003	0.093	0.019	0.893
IL-8 (pg/mL)	8.17 ± 0.65	6.70 ± 0.56	7.02 ± 0.75	0.241	0.037	0.738	0.96
TNF-α (pg/mL)	10.72 ± 0.47	9.76 ± 0.67	9.27 ± 0.64	0.201	0.088	0.605	0.234
MMP-2 (ng/mL)	120,317 ± 5,068	106,524 ± 5,010	95,434 ± 5,691	0.004	0.003	0.148	0.256
MMP-9 (ng/mL)	258,804 ± 15,582	245,000 ± 18,292	221,371 ± 20,436	0.333	0.240	0.392	0.565

Table 2. Cyclophilins and Inflammatory Markers

Controls

Coronary artery disease

P value

Chronic

Acute

Between three groups

CAD vs. controls

Chronic CAD vs. acute CAD

Chronic CAD vs. controls

CAD: coronary artery disease; Cyp: cyclophilin; IFN-γ: interferon γ; IL: interleukin; TNF-α: tumor necrosis factor α; MMP: metalloproteinase; SEM: standard error of the mean. Data values are shown as mean ± SEM. Significant differences: P < 0.05.

Cyclophilins (Cyps)

CypA (ng/mL)

2.53 ± 0.53

5.52 ± 0.759

7.80 ± 1.30

< 0.001

0.134

0.001

CypB (pg/mL)

140.2 ± 32.7

181.0 ± 28.2

208.8 ± 44.8

0.387

0.204

0.601

0.353

CypC (pg/mL)

9.38 ± 1.5

30.56 ± 4.7

34.28 ± 5.8

< 0.001

0.620

< 0.001

CypD (pg/mL)

125.14 ± 20.5

117.74 ± 11.5

97.68 ± 10.7

0.433

0.431

0.205

0.756

CypC > 17.5 (pg/mL)

13.3% (6)

57.5% (29)

72.5% (23)

< 0.001

0.245

< 0.001

Inflammatory markers

IFN-γ (pg/mL)

34.3 ± 2.8

27.5 ± 2.4

27.4 ± 2.7

0.102

0.032

0.989

0.73

IL-1β (pg/mL)

2.71 ± 0.17

3.94 ± 0.42

3.73 ± 0.37

0.012

0.001

0.695

0.009

IL-2 (pg/mL)

4.38 ± 0.44

4.87 ± 0.52

4.97 ± 0.51

0.648

0.356

0.891

0.473

IL-6 (pg/mL)

4.04 ± 0.33

3.95 ± 0.59

8.08 ± 1.59

0.003

0.093

0.019

0.893

IL-8 (pg/mL)

8.17 ± 0.65

6.70 ± 0.56

7.02 ± 0.75

0.241

0.037

0.738

0.96

TNF-α (pg/mL)

10.72 ± 0.47

9.76 ± 0.67

9.27 ± 0.64

0.201

0.088

0.605

0.234

MMP-2 (ng/mL)

120,317 ± 5,068

106,524 ± 5,010

95,434 ± 5,691

0.004

0.003

0.148

0.256

MMP-9 (ng/mL)

258,804 ± 15,582

245,000 ± 18,292

221,371 ± 20,436

0.333

0.240

0.392

0.565

**Table 3.** Univariate Analysis of CypC ≥ 17.5 pg/mL: Clinical Characteristics
	CypC < 17.5	CypC ≥ 17.5	P value
LVEF: left ventricular ejection fraction; AAS: acetylsalicylic acid; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft. Significant differences: P < 0.05.
Gender (male)	68.1% (47)	21.4% (12)	0.191
Age	52.8 ± 1.8	64.0 ± 1.6	< 0.001
LVEF (%)	54.4 ± 2.1	55.3 ± 1.3	0.697
Cardiovascular risk factors
Hypertension	27.5% (19)	48.2% (27)	0.017
Dyslipidemia	36.2% (25)	69.6% (39)	< 0.001
Active smoker	16.2% (11)	23.2% (13)	0.324
Diabetes	13.0% (9)	21.4% (12)	0.212
Family history of CAD	15.8% (6)	15.4% (8)	0.958
Medications
AAS	23.2% (16)	37.5% (21)	0.081
Clopidogrel	1.4% (1)	12.5% (7)	0.022
Statins	36.2% (25)	48.2% (27)	0.176
Coronary artery disease
Yes	42.0% (29)	91.1% (51)	< 0.001
No	58.0% (40)	8.9% (5)
Number of coronary artery vessels with significant stenosis
0	58.0% (40)	10.7% (6)	< 0.001
1	21.7% (15)	32.1% (18)
2	7.2% (5)	28.6% (16)
3	13.0% (9)	28.6% (16)
Type of coronary artery revascularization
None	58.0% (40)	16.1% (9)	< 0.001
PCI	40.6% (28)	75.0% (42)
CABG	1.4% (1)	8.9% (5)
Complete coronary artery revascularization
No	72.5% (50)	55.4% (31)	0.46
Yes	27.5% (19)	44.6% (25)
Readmission for coronary artery disease
No	82.8% (24)	80.4% (41)	0.794
Yes	17.2% (5)	19.6% (10)

Table 3. Univariate Analysis of CypC ≥ 17.5 pg/mL: Clinical Characteristics

CypC < 17.5

CypC ≥ 17.5

P value

LVEF: left ventricular ejection fraction; AAS: acetylsalicylic acid; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft. Significant differences: P < 0.05.

Gender (male)

68.1% (47)

21.4% (12)

0.191

Age

52.8 ± 1.8

64.0 ± 1.6

< 0.001

LVEF (%)

54.4 ± 2.1

55.3 ± 1.3

0.697

Cardiovascular risk factors

Hypertension

27.5% (19)

48.2% (27)

0.017

Dyslipidemia

36.2% (25)

69.6% (39)

< 0.001

Active smoker

16.2% (11)

23.2% (13)

0.324

Diabetes

13.0% (9)

21.4% (12)

0.212

Family history of CAD

15.8% (6)

15.4% (8)

0.958

Medications

AAS

23.2% (16)

37.5% (21)

0.081

Clopidogrel

1.4% (1)

12.5% (7)

0.022

Statins

36.2% (25)

48.2% (27)

0.176

Coronary artery disease

Yes

42.0% (29)

91.1% (51)

< 0.001

58.0% (40)

8.9% (5)

Number of coronary artery vessels with significant stenosis

58.0% (40)

10.7% (6)

< 0.001

21.7% (15)

32.1% (18)

7.2% (5)

28.6% (16)

13.0% (9)

28.6% (16)

Type of coronary artery revascularization

None

58.0% (40)

16.1% (9)

< 0.001

PCI

40.6% (28)

75.0% (42)

CABG

1.4% (1)

8.9% (5)

Complete coronary artery revascularization

72.5% (50)

55.4% (31)

0.46

Yes

27.5% (19)

44.6% (25)

Readmission for coronary artery disease

82.8% (24)

80.4% (41)

0.794

Yes

17.2% (5)

19.6% (10)

**Table 4.** Multivariate Analysis: CypC > 17.5 pg/mL and Related Factors With Presence of CAD
	OR	OR CI 95%	P value
CypC: cyclophilin C; LDL: low-density lipoprotein; TG: triglycerides; OR: odds ratio; OR CI 95%: odds ration confidence interval 95%. Significant differences: P < 0.05.
Model 1: CypC > 17.5 and clinical variables
CypC > 17.5	56.808	4.85 - 665	0.001
Age	1.153	1.05 - 1.26	0.002
Gender (male)	45.4	3.13 - 498	0.005
Hypertension	13.044	1.25 - 135	0.032
Dyslipidemia	9.420	1.55 - 57.1	0.015
Smoker	18.616	1.75 - 198	0.015
Model 2: CypC > 17.5 and analytical variables
CypC > 17.5	22.6	3.77 - 136	0.001
Total cholesterol	0.830	0.751 - 0.918	0.001
LDL	1.170	1.05 - 1.30	0.003
TG	1.051	1.03 - 1.08	0.000
Model 3: CypC > 17.5 and clinical and analytical variables
CypC > 17.5	30.7	3.85 - 245	0.001
Total cholesterol	0.963	0.938 - 0.989	0.005
Gender (male)	40.7	4.32 - 383	0.001
Age	1.215	1.095 - 1.348	< 0.001

Table 4. Multivariate Analysis: CypC > 17.5 pg/mL and Related Factors With Presence of CAD

OR CI 95%

P value

CypC: cyclophilin C; LDL: low-density lipoprotein; TG: triglycerides; OR: odds ratio; OR CI 95%: odds ration confidence interval 95%. Significant differences: P < 0.05.

Model 1: CypC > 17.5 and clinical variables

CypC > 17.5

56.808

4.85 - 665

0.001

Age

1.153

1.05 - 1.26

0.002

Gender (male)

45.4

3.13 - 498

0.005

Hypertension

13.044

1.25 - 135

0.032

Dyslipidemia

9.420

1.55 - 57.1

0.015

Smoker

18.616

1.75 - 198

0.015

Model 2: CypC > 17.5 and analytical variables

CypC > 17.5

22.6

3.77 - 136

0.001

Total cholesterol

0.830

0.751 - 0.918

0.001

LDL

1.170

1.05 - 1.30

0.003

1.051

1.03 - 1.08

0.000

Model 3: CypC > 17.5 and clinical and analytical variables

CypC > 17.5

30.7

3.85 - 245

0.001

Total cholesterol

0.963

0.938 - 0.989

0.005

Gender (male)

40.7

4.32 - 383

0.001

Age

1.215

1.095 - 1.348

< 0.001